Cefuroxime axetil is a cephalosporin antibiotic having a high activity against a wide spectrum of Gram-positive and Gram-negative microorganisms. It shows polymorphism of three forms: a crystalline form having a melting point of about 180.degree. C., a substantially amorphous form having a high melting point of about 135.degree. C. and a substantially amorphous form having a low melting point of about 70.degree. C. The crystalline form of cefuroxime axetil, which is slightly soluble in water and forms a gel upon contact with an aqueous medium, is not readily absorbable in the gastro-intestinal tract, rendering its bioavailability on oral administration very low.
U.S. Pat. No. 4,820,833 discloses a process for preparing a highly pure, substantially amorphous form of cefuroxime axetil from the crystalline form, for the purpose of improving the solubility of the drug. The substantially amorphous form of cefuroxime axetil with a low-melting point has a higher water-solubility than the crystalline form. However, it forms a thick gel upon contact with an aqueous medium, thereby causing handling problems in the process for a preparing pharmaceutical composition therefrom. Moreover, the above process is hampered by the problem of a low yield of about 70%, which is caused by the stickiness of the amorphous product.
Further, Korean Patent Publication No. 94-233 teaches a rapidly disintegratable film-coated tablet comprising a core of amorphous cefuroxime axetil and a coating film having a rupture time of less than 40 seconds, which is developed for the purpose of preventing the gelation of cefuroxime axetil in an aqueous medium and also for masking the bitter taste of the drug. This tablet is commercially available as Zinnat.RTM. tablet marketed by Glaxo Group Limited (London, England). However, this tablet has a problem in that the bioavailability of cefuroxime axetil may be deteriorated when the rupture time of the coating film is not strictly regulated.
PCT International Publication No. WO 99/08683 discloses a co-precipitate comprising the low-melting point amorphous form of cefuroxime axetil and a water-soluble excipient, e.g., povidone. The co-precipitate is useful for the preparation of a tablet which is not limited by the rupture time of the coating film. However, this co-precipitate undergoes an undesirable property change as it readily absorbs moisture due to the presence of the water-soluble excipient. Further, the co-precipitate, which has high adhesiveness and poor fluidity, is difficult to handle in a spray-drying process and, accordingly, the yield of co-precipitate produced by the disclosed method is low, e.g., about 70%.
Generally, water molecules absorbed by a drug may exist in three forms: weakly adsorbed water on the surface of the drug which is readily evaporizable; water bound to the drug more strongly than the surface water which causes a change in the physicochemical properties, e.g., the melting point, of the drug; and crystal water incorporated in a lattice structure of the drug crystal.
Thermal analysis conducted by the present inventors reveals that the co-precipitate of PCT International Publication No. WO 99/08683 shows a shift in the absorption peak temperature under a moist condition and this shifted peak reverted to the original position under a dry condition. Accordingly, the water adsorbed on the co-precipitate is judged to be bound water which causes a physicochemical change of the drug. Further, despite the use of a water-soluble excipient, the dissolution of cefuroxime axetil from the co-precipitate is not facilitated significantly and, accordingly, the bioavailability of cefuroxime axetil contained in the co-precipitate is relatively low.
The present inventors have endeavored to solve the problems associated with the existing substantially amorphous form of cefuroxime axetil with a low-melting point and succeeded in developing an improved non-crystalline cefuroxime axetil composition having a high stability and bioavailability.